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Molecular Function and Contribution of TBX4 in Development and Disease.

ABSTRACT: Over the past decade, recognition of the profound impact of the TBX4 (T-box 4) gene, which encodes a member of the evolutionarily conserved family of T-box-containing transcription factors, on respiratory diseases has emerged. The developmental importance of TBX4 is emphasized by the association of TBX4 variants with congenital disorders involving respiratory and skeletal structures; however, the exact role of TBX4 in human development remains incompletely understood. Here, we discuss the developmental, tissue-specific, and pathological TBX4 functions identified through human and animal studies and review the published TBX4 variants resulting in variable disease phenotypes. We also outline future research directions to fill the gaps in our understanding of TBX4 function and of how TBX4 disruption affects development.

SUBMITTER: Karolak JA

PROVIDER: S-EPMC10111992 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Molecular Function and Contribution of TBX4 in Development and Disease.

Karolak Justyna A JA Welch Carrie L CL Mosimann Christian C Bzdęga Katarzyna K West James D JD Montani David D Eyries Mélanie M Mullen Mary P MP Abman Steven H SH Prapa Matina M Gräf Stefan S Morrell Nicholas W NW Hemnes Anna R AR Perros Frédéric F Hamid Rizwan R Logan Malcolm P O MPO Whitsett Jeffrey J Galambos Csaba C Stankiewicz Paweł P Chung Wendy K WK Austin Eric D ED

American journal of respiratory and critical care medicine 20230401 7

Over the past decade, recognition of the profound impact of the TBX4 (T-box 4) gene, which encodes a member of the evolutionarily conserved family of T-box-containing transcription factors, on respiratory diseases has emerged. The developmental importance of TBX4 is emphasized by the association of TBX4 variants with congenital disorders involving respiratory and skeletal structures; however, the exact role of TBX4 in human development remains incompletely unde ...[more]

PMID: 36367783

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Project description:Rationale: Despite the increased recognition of TBX4 (T-BOX transcription factor 4)-associated pulmonary arterial hypertension (PAH), genotype-phenotype associations are lacking and may provide important insights. Objectives: To compile and functionally characterize all TBX4 variants reported to date and undertake a comprehensive genotype-phenotype analysis. Methods: We assembled a multicenter cohort of 137 patients harboring monoallelic TBX4 variants and assessed the pathogenicity of missense variation (n = 42) using a novel luciferase reporter assay containing T-BOX binding motifs. We sought genotype-phenotype correlations and undertook a comparative analysis with patients with PAH with BMPR2 (Bone Morphogenetic Protein Receptor type 2) causal variants (n = 162) or no identified variants in PAH-associated genes (n = 741) genotyped via the National Institute for Health Research BioResource-Rare Diseases. Measurements and Main Results: Functional assessment of TBX4 missense variants led to the novel finding of gain-of-function effects associated with older age at diagnosis of lung disease compared with loss-of-function effects (P = 0.038). Variants located in the T-BOX and nuclear localization domains were associated with earlier presentation (P = 0.005) and increased incidence of interstitial lung disease (P = 0.003). Event-free survival (death or transplantation) was shorter in the T-BOX group (P = 0.022), although age had a significant effect in the hazard model (P = 0.0461). Carriers of TBX4 variants were diagnosed at a younger age (P < 0.001) and had worse baseline lung function (FEV1, FVC) (P = 0.009) than the BMPR2 and no identified causal variant groups. Conclusions: We demonstrated that TBX4 syndrome is not strictly the result of haploinsufficiency but can also be caused by gain of function. The pleiotropic effects of TBX4 in lung disease may be in part explained by the differential effect of pathogenic mutations located in critical protein domains.

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Molecular Function and Contribution of TBX4 in Development and Disease.

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Molecular Function and Contribution of <i>TBX4</i> in Development and Disease.

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Dataset Information

Molecular Function and Contribution of TBX4 in Development and Disease.

Publications

Molecular Function and Contribution of &lt;i&gt;TBX4&lt;/i&gt; in Development and Disease.

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OmicsDI is part of the ELIXIR infrastructure

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Molecular Function and Contribution of <i>TBX4</i> in Development and Disease.